Altered Expression of a Unique Set of Genes Reveals Complex Etiology of Schizophrenia

Kumar, Ashutosh; Pareek, Vikas; Singh, Himanshu Narayan; Faiq, Muneeb A.; Narayan, Ravi Kant; Raza, Khursheed; Kumar, Pavan

doi:10.3389/fpsyt.2019.00906

Cited by 8 publications

(6 citation statements)

References 56 publications

(57 reference statements)

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“…Since metabolic anomalies were associated with SZ ( Kumar et al, 2019 ), we also evaluated the expression of ATP5 , coding for mitochondrial-membrane ATP synthase. ATP5 expression decreased throughout the evaluated period in HC networks, but remained unchanged in SZ ( Supplementary Figure S1 , Supplementary Table S2 ).…”

Section: Resultsmentioning

confidence: 99%

Altered resting-state functional connectivity in hiPSCs-derived neuronal networks from schizophrenia patients

Puvogel

Blanchard

Casas

et al. 2022

Front. Cell Dev. Biol.

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Schizophrenia (SZ) is a severe mental disorder that arises from abnormal neurodevelopment, caused by genetic and environmental factors. SZ often involves distortions in reality perception and it is widely associated with alterations in brain connectivity. In the present work, we used Human Induced Pluripotent Stem Cells (hiPSCs)-derived neuronal cultures to study neural communicational dynamics during early development in SZ. We conducted gene and protein expression profiling, calcium imaging recordings, and applied a mathematical model to quantify the dynamism of functional connectivity (FC) in hiPSCs-derived neuronal networks. Along the neurodifferentiation process, SZ networks displayed altered gene expression of the glutamate receptor-related proteins HOMER1 and GRIN1 compared to healthy control (HC) networks, suggesting a possible tendency to develop hyperexcitability. Resting-state FC in neuronal networks derived from HC and SZ patients emerged as a dynamic phenomenon exhibiting connectivity configurations reoccurring in time (hub states). Compared to HC, SZ networks were less thorough in exploring different FC configurations, changed configurations less often, presented a reduced repertoire of hub states and spent longer uninterrupted time intervals in this less diverse universe of hubs. Our results suggest that alterations in the communicational dynamics of SZ emerging neuronal networks might contribute to the previously described brain FC anomalies in SZ patients, by compromising the ability of their neuronal networks for rapid and efficient reorganization through different activity patterns.

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Section: Resultsmentioning

confidence: 99%

Altered resting-state functional connectivity in hiPSCs-derived neuronal networks from schizophrenia patients

Puvogel

Blanchard

Casas

et al. 2022

Front. Cell Dev. Biol.

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“…Our finding that hypomethylation of cg23712970 in ACIN1 and PDCD10 may result in increased expression of these genes is partially consistent with the recent finding that expression levels of the BCL2 and CASP3 apoptosis genes were significantly higher in the peripheral blood lymphocytes of schizophrenic patients [ 44 ]. Analysis of mRNA expression in the post-mortem brain tissue of patients with SZ also revealed altered mRNA expression in the IFITM2, TIAL1, PDCD6, and MCL genes, which are involved in programmed cell death [ 45 ]. ATG4B is another gene involved in autophagy.…”

Section: Discussionmentioning

confidence: 99%

Methylome-wide Association Study of Patients with Recent-onset Psychosis

Piao

Cui

Rami

et al. 2022

Clin Psychopharmacol Neurosci

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Objective: Dysregulation of gene expression through epigenetic mechanisms may have a vital role in the pathogenesis of schizophrenia (SZ). In this study, we investigated the association of altered methylation patterns with SZ symptoms and early trauma in patients and healthy controls. Methods: The present study was conducted to identify methylation changes in CpG sites in peripheral blood associated with recent-onset (RO) psychosis using methylome-wide analysis. Lifestyle factors, such as smoking, alcohol, exercise, and diet, were controlled. Results: We identified 2,912 differentially methylated CpG sites in patients with RO psychosis compared to controls. Most of the genes associated with the top 20 differentially methylated sites had not been reported in previous methylation studies and were involved in apoptosis, autophagy, axonal growth, neuroinflammation, protein folding, etc. The top 15 significantly enriched Kyoto Encyclopedia of Genes and Genomes pathways included the oxytocin signaling pathway, long-term depression pathway, axon guidance, endometrial cancer, long-term potentiation, mitogen-activated protein kinase signaling pathway, and glutamatergic pathway, among others. In the patient group, significant associations of novel methylated genes with early trauma and psychopathology were observed. Conclusion: Our results suggest an association of differential DNA methylation with the pathophysiology of psychosis and early trauma. Blood DNA methylation signatures show promise as biomarkers of future psychosis.

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“…Since metabolic anomalies have been associated to SZ [38], we also evaluated the expression of ATP5, coding for mitochondrial-membrane ATP synthase. ATP5 expression decreased in the same time interval in HC networks, but did not change in SZ ones (Figure 1S, Table S3).…”

Section: Altered Expression Of Genes Involved In Synaptic Function and Network Establishment During Sz Neurodevelopmentmentioning

confidence: 99%

Altered resting-state functional connectivity in hiPSC-derived neuronal networks from schizophrenia patients

Puvogel

Blanchard

Casas

et al. 2021

Preprint

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Schizophrenia (SZ) is a complex mental disease thought to arise from abnormal neurodevelopment, characterized by an altered reality perception and widely associated with brain connectivity anomalies. Previous work has shown disrupted resting-state brain functional connectivity (FC) in SZ patients. We used Human Induced Pluripotent Stem Cells (hiPSC)-derived neuronal cultures to study SZ's neural communicational dynamics during early development. We conducted gene and protein expression profiling, calcium imaging and mathematical modeling to evaluate FC. Along the neurodifferentiation process, SZ networks displayed altered expression of genes related to synaptic function, cell migration and cytoskeleton organization, suggesting alterations in excitatory/inhibitory balance. Resting-state FC in neuronal networks derived from healthy controls (HC) and SZ patients emerged as a dynamic phenomenon exhibiting "hub-states", which are connectivity configurations reoccurring in time. Compared to HC, SZ networks were less thorough in exploring different FC configurations, changed configurations less often, presented a reduced repertoire of hub-states and spent longer uninterrupted time intervals in this less diverse universe of hubs. Our observations at a single cell resolution may reflect intrinsic dynamical principles ruling brain activity at rest and highlight the relevance of identifying multiscale connectivity properties between functional brain units. We propose that FC alterations in SZ patients are a consequence of an abnormal early development of synaptic communication dynamics, compromising network's ability for rapid and efficient reorganization of neuronal activity patterns. Remarkably, these findings mirror resting-state brain FC in SZ patients, laying the groundwork for future studies among such different spatiotemporal domains, as are brains and neurons, in both health and disease.

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Altered Expression of a Unique Set of Genes Reveals Complex Etiology of Schizophrenia

Cited by 8 publications

References 56 publications

Altered resting-state functional connectivity in hiPSCs-derived neuronal networks from schizophrenia patients

Altered resting-state functional connectivity in hiPSCs-derived neuronal networks from schizophrenia patients

Methylome-wide Association Study of Patients with Recent-onset Psychosis

Altered resting-state functional connectivity in hiPSC-derived neuronal networks from schizophrenia patients

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